Endothelial cell injury is hypothesized to be an early event in the development of atherosclerosis. This laboratory has shown that elevated levels of very-low-density lipoproteins (VLDL, d less than 1.006 g/ml) injure porcine aortic endothelial cells in vitro. In contrast to the results obtained with rat serum, elevated levels of VLDL in huamn serum are not toxic to porcine aortic endothelial cells in vitro. This laboratory has found that human VLDL are indeed toxic when incubated in the absence of human serum or when added to rat serum. Elevated levels of VLDL are not toxic when human serum is present. Human serum was found to contain specific proteins factor, Toxicity Preventing Activity (TxPA) which offsets the toxicity of elevated levels of VLDL in vitro. The level of TxPA is significantly decreased in the serum of individuals with angiographically documented coronary artery disease, indicating that it may be a new protective factor for coronary artery disease. When the level of this new factor is combined with lipoprotein levels an atherogenic index can be derived which classifies angiographed individuals with an accuracy of greater than 93% in the two clinical studies. This atherogenic index is likely to be clinically useful since it provides a means of identifying atherosclerosis prone individuals before they develop symptoms of the disease. Appropriate dietary and/or drug regimens could be instituted to lessen or prevent the development of atherosclerosis in these individuals. Individuals who are not at risk would be freer to choose diets and lifestyles which suit their individual preferences. In this proposal I would like to continue efforts to isolate and characterize this factor as well as to understand the mechanism of its action in preventing VLDL toxicity.